Control of differentiation

Although it would be desirable to have better control over ES cell differentiation, the ability to dedifferentiate cells is particularly sought in the human context. This is because currently the only satisfactory route known to the generation of ES cells is from an early embryo. Immunohistocompatible isogenic hES cells could be tailormade for a particular patient by nuclear transfer of a self-donated somatic cell into an enucleated oocyte, but this raises both practical and regulatory issues.

It is self-evident that at the earliest stages of development there will be dividing populations of cells that have a broad potential developmental fate. Experimental embryology has shown that this fate becomes progressively restricted as cell lineages develop. It is not self-evident however at which, if any, stages along this progression from totipotential to single lineage restriction the cells may cycle

Figure 1 Interactions and factors maintaining and controlling the differentiative state of a cell. Cellular level -A: nucleocytoplasmic interactions, B: maintenance and growth factors produced endogenously, C: external factors interacting with cell surface receptors, D: external factors interacting with nuclear receptors (possible after specific transport). Chromosomal level - E: transcription factors, F: DNA methylation, G: histone acetylation, H: histone methylation, I: chromatin packing. For many cells these interactions take place in populations (homoiogenic induction-community effect) and in specific 'niches'.

mitotically and keep their developmental fate statically intact. Indeed, this question is intimately bound up with our understanding of the stability of cell determination and the maintenance of the differentiated state. A precursor population is not the same as a stem cell population. In addition, stem cells both during development and in adult organisms reside in specific conditions, in niches; and it is not necessarily straightforward to maintain or replicate the niche conditions in isolation, in vitro. In order to isolate and maintain stem cells such conditions need to be provided, or their necessity obviated by other means. Another factor to be considered is that in some adult conditions stem cells may represent very slowly growing reserve populations that give rise to transit committed populations, in which the amplification of rapid cell division occurs.

A full understanding of these processes and of the conditions under which they may take place will be desirable in order to have full manipulative control over cellular commitment and differentiation. Indeed, if and when we have this practical manipulative ability to dedifferentiate and, at will, to redifferentiate cells, there will be no need for the isolation of ES cells directly from an embryo. This would remove all the ethical considerations which apply to the use of hES cells (5). There is, however, a long way to go. Some of the areas that need to be explored are set out in the annotated diagram above (Figure 1).

The differentiated state of a cell is the result of a series of developmental steps, each of which typically narrows the prospective fate of the cell and its descendants. This is, in most cases, an irreversible restriction although there are some

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